We have engineered a synthetic antibody that neutralizes 100% of HIV strains. This antibody is built from the parts of CD4 and CCR5 that are recognized by HIV, and is named eCD4-Ig. The goal of our research program is now to maximize its efficacy. A fundamental question for our effort-and for the field as a whole-is: Which isotype of IgG has the properties that are most important for suppressing viral replication? To answer this question, we will eliminate problematic features of IgG2 and IgG3 that have historically presented a barrier to their use as therapeutics in humans, and we will compare the ability of rhesus IgG1, IgG2, and IgG3 forms of eCD4-Ig to suppress SIV replication in macaques. The isotype of eCD4-Ig that most completely suppresses viral replication will be advanced to human clinical trials.